Molecular pathogenesis and targets for therapy in myelodysplastic syndrome (MDS) and MDS-related leukemias.
The myelodysplastic syndromes (MDS) are a family of disorders that are characterized by ineffective hematopoiesis and evolution to acute myelogenous leukemias (AMLs) that are strikingly refractory to current therapeutic approaches. A substantial proportion of these complex diseases arise in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder (secondary MDS/AML). On the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation in hematopoietic precursors. In addition, MDS cells display impaired responses to diverse cytokines in terms of activating signaling intermediaries that trigger both proliferation and differentiation, and the disruption of the normal flow of biochemical information along the pathways translates into ineffective multilineage hematopoiesis and bone marrow failure. MDS/AMLs provide a fertile testing ground for the development of novel agents and the concomitant molecular dissection of the mechanisms by which these agents induce growth inhibition, terminal differentiation, and eventual cell death.
Karp
J E
JE
Greenebaum Cancer Center, University of Maryland Medical Systems, Baltimore 21201, USA.
D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D009190:Myelodysplastic Syndromes / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy